The present invention is based upon the phenomenon that oxygen has a quenching effect on the molecular luminescence of various chemical compounds and that this effect can be employed for imaging oxygen concentrations (partial pressure) in vivo. Animals, especially mammals, are dependent upon having adequate oxygen supplies in their body tissues. In mammals, the circulatory system employs specialized oxygen-carrying molecules in the blood to deliver oxygen from the lungs to other tissues throughout the body. Thus, every organ in the body contains oxygen in varying amounts and concentrations in every tissue, and information regarding the distribution and concentration of oxygen in tissue can be indicative of structure, anomalies, defects or disease.
For example, in traumatic injury, the primary threat to life is often the loss of blood and the resulting hemorrhagic shock and hypotension, under-perfusion of tissue and abnormal the blood flow among and within the tissues. As a result, regions of tissue become hypoxic, or relatively devoid of oxygen. Loss of blood volume is usually treated by plasma expanders, in an effort to maintain blood pressure, and to improve oxygen delivery to the tissue until surgery can be performed, and following repair, oxygen levels can offer a measure of efficacy. See, for example, U.S. Pat. Nos. 5,593,899 and 4,947,850 which disclose methods and apparatus for imaging internal body structures and measuring oxygen dependent quenching of phosphorescence.
Fiber-optic sensors have been used to measure oxygen levels in vivo by positioning an analyte-sensitive indicator molecule in a light path at a desired measurement site. Typically, the optical fiber transmits electromagnetic radiation from a light source to the indicator molecule, and the reflectance from or absorption of light by the indicator molecule gives an indication of the gaseous or ionic concentration of the analyte. Alternatively, for monitoring an analyte, such as oxygen, the optical fiber transmits electromagnetic radiation to the indicator molecule, exciting it into a type of luminescence, i.e., phosphorescence, and the level and/or duration of phosphorescence by the indicator molecule serves as an indication of the concentration of the gas in the surrounding fluid. In the prior art sensors, the indicator molecules are typically disposed in a sealed chamber at the distal end of an optical fiber, and the chamber walls are permeable to the analytes of interest.
Several sensor devices are known which are useful for measuring oxygen and pH content in human and animal tissues by insertion of a light-sensing, optical fiber probe into a blood vessel of the subject. See, for example, U.S. Pat. No. 5,830,138 providing a detection device for measuring tissue oxygen and/or pH(CO2) via insertion of a probe into a blood vessel of a subject in vivo, wherein the probe comprises a fiber optic means enclosed within a gas-permeable film. Situated between the gas-permeable film and the fiber optic means is a reservoir of a liquid, containing an aqueous oxygen-quenchable, phosphorescence-emitting oxygen sensor and/or a fluorescence-emitting pH sensor, and further comprising a means for detecting phosphorescent and/or fluorescent excitation light.
U.S. Pat. No. 4,758,814 provides an optical fiber covered by a membrane constructed of a hydrophilic porous material containing a pH sensitive dye for measuring blood pH levels, and having embedded in the membrane several hydrophobic microspheres containing a fluorescent dye quenchable by oxygen to simultaneously or sequentially measure oxygen partial pressure. Another fluorometric oxygen sensing device is described in U.S. Pat. No. 5,012,809, wherein the fluorometric sensor is constructed with silicone polycarbonate bonded to one or more plastic fiber optic light pipes using polymethylmethacrylate glues. U.S. Pat. No. 5,127,405 provides another version of a fiber optic probe containing an oxygen-permeable transport resin embedded with a luminescent composition comprising crystals of an oxygen quenchable phosphorescent material, whereby frequency domain representations are used to derive values for luminescence lifetimes or decay parameters. U.S. Pat. No. 4,752,115 employs an optical fiber, 250 nm in diameter or small enough for insertion into veins and/or arteries, wherein the probe is coated with an oxygen sensitive (oxygen quenchable) fluorescent dye which fluoresces light back to measure regional oxygen partial pressure, and wherein the oxygen sensing end of the probe may further include a gas-permeable sleeve over the optical fiber.
U.S. Pat. No. 4,476,870 discloses a fiber optic probe for implantation in the human body for gaseous oxygen measurement in the blood stream by means of a probe employs oxygen quenchable dye fluorescence enveloped in a hydrophobic, gas-permeable material at the end of two 150 um strands of a plastic optical fiber. U.S. Pat. No. 4,200,110 discloses a fiber optic pH probe employing an ion-permeable membrane envelope enclosing the ends of a pair of optical fibers, with a pH sensitive dye indicator composition disposed within the envelope. U.S. Pat. Nos. 3,814,081 and 3,787,119 describe early versions of such probes using photosensitive cells to determine physical and chemical characteristics of blood in vivo by direct measurement of light, but without oxygen quenchable phosphor/fluorophor compounds.
However, while the prior art probes are intended for measuring “tissue oxygen” in a patient in vivo, they require insertion into the lumen of a blood vessel and actually measure blood gases, not oxygen in the tissue surrounding the vessel. Blood flow rapidly changes the oxygen level within a given point in the vessel and would offer no way of measuring tissue oxygen in, for example, necrosing tissue. Nor can the prior art systems be effective in regions not supplied with large vessels, such as muscle tissue, or in damaged tissue areas where the blood vessels are no longer intact, as in emergency situations.
One structural problem with the prior art sensing systems of the type described for use in blood vessels, is that the structure of the chambers and probe configuration often encourage the formation of blood clots or thrombi. Particularly when multiple fibers are used to determine several blood gas parameters, such as oxygen, carbon dioxide, and pH together, the probe provides interfiber crevices that encourage thrombi formation. Furthermore, the complexity and difficulty of manufacturing multi-fiber probes is well known, due to the small diameters of the fibers and requirements of their arrangement. Such probes must be small enough to fit within a blood vessel while still permitting blood to flow, especially problematic for neonatal or pediatric applications in which the patient's veins or arteries may be too small in diameter for insertion of the probe assembly.
Moreover, correctly placing the sensing end of the probe in the blood vessel and maintaining that placement for continued monitoring is important for obtaining reliable blood gas results. The prior art tissue oxygen or multianalyte sensors have failed to effectively deal with the problems set forth above, and none offer a method for measuring oxygen in tissue other than via a blood vessel.
The design of the prior art probes is distinctly different from a device that can directly measure analyte levels in tissue, although similar sensor compositions and detection monitors may be used. A tissue probes that is not protected by a blood vessel, must withstand much higher local tissue pressures. For example, if prior art probes were inserted directly into tissue, rather than into a blood vessel, they would collapse or be disabled under the pressure of the surrounding tissue. They lack sufficient wall strength to withstand tissue pressure without the protection of a blood vessel and a surrounding fluid environment. Consequently, without the protection by the blood and blood vessel, insertion of a prior art probe directly into a non-fluid, tissue environment could compress and damage the sensor chamber, resulting in failure or a significantly decreased excitation of a phosphor sensor, as well as decreased collection of the returned phosphorescent excitation light. Side pressures could further cause sharp bends or “kinks” immediately adjacent to the optical fibers, which must be accounted for in the probe design.
Thus, until the present invention there has remained a need in the art to provide an improved device and method for directly, rapidly and accurately measuring oxygen levels in tissue, particularly in vivo. However, such information would be highly beneficial as a diagnostic tool, and would facilitate the quick, accurate and precise identification of many otherwise difficult-to-diagnose maladies or detecting life-threatening situations.